Discussion

Reimbursement for trial participation remains controversial, with limited guidance for investigators in South Africa and developed countries in recent years.2 ,12 Investigator's opinion may be influenced by anecdotal experiences with some trial participants, where the primary interest in participation is driven by financial gain, and may constitute an undue inducement for indigent participants. A South African trial (n=250) documenting participant opinion on reimbursements in clinical trials sought to clarify the amount of money that would constitute an undue inducement.2 Although 66.5% were unemployed and 64.0% were dependent on the state alone for healthcare, 93.6% indicated that they would still participate in a clinical trial if they received no reimbursement.2 However, 74.0% felt that participants should receive reimbursement, mostly to cover travel expenses, with only 6.4% reporting use of reimbursement for necessities.2 The CAPRISA 008 participants mostly reported interest in gaining post-trial access to the gel to reduce HIV risk, but were challenged to do so given the cost of transport, the duration of ‘standard of care’ visits, uncompensated time off work and lack of recognition for contribution to science.

A review of seven studies in developed countries found that financial remuneration was a significant motivator for volunteering among normal healthy volunteers.4 The assumption was that the benefits to normal healthy volunteers in a clinical trial are limited, and thus, could not influence the decision to participate.4 CAPRISA 008 is a post-trial access implementation trial, using an unlicensed product where the phase IIb proof-of-concept trial has shown safety and 39.0% efficacy7; participants are healthy women at high risk of HIV acquisition who will benefit personally from post-trial access to an effective product; the thinking of the protocol team when the protocol was first submitted for regulatory review was that for ‘standard of care’ visits, reimbursement to cover the cost of travel to and from the research clinics only was sufficient. In fact, the primary motivator in CAPRISA 008 participants remains access to study product, with financial remuneration expected to cover personal travel costs, time and inconvenience, as well as recognition for their participation in a trial.

The recommendation when deciding whether to offer reimbursement is that investigators should take into account the nature of the study, the nature of participant contributions and vulnerabilities, institutional or organisational guidelines and local societal and cultural norms.1 CAPRISA 008 initially took into account the study design, assigning a lower reimbursement for ‘standard of care’ visits, given the superior staffing to client ratios and the provision of above standard of care service in research versus public sector clinics. Standard of care service provision in the trial exceeds that in the public sector, in that Papanicolaou (Pap) smears are offered to all participants irrespective of age, updated research findings on available contraception is communicated to participants and an expanded method mix is strongly promoted, and all sexual reproductive services, including HIV testing and counselling and management of minor ailments are provided by the same healthcare provider in one visit. Thus, the time spent in the clinic and the inconvenience of the procedures done at these visits do not exceed what is normally experienced in a public sector clinic. However, the research team did not factor in the additional time spent travelling to and from the designated clinics or the impact that the protracted approval process and resultant changes in inflation and the costs of living had on transport costs, prior to study initiation. Thus, a reimbursement rate appropriate to a visit 2 years previously was implemented 2 years later, without adjustment. Prior to this event, CAPRISA, like many other research organisations in South Africa, implemented the MCC-recommended flat-rate reimbursement of rands 150 per visit. The resultant participant dissatisfaction and negative impact on early recruitment and retention culminated in the review of this standard, the adaptation of the NHREC guideline and the development of an institution-wide draft policy for participant reimbursement for all trials, based on time, inconvenience and expenses, using the national unskilled labour remuneration rates to calculate the amount to be paid for time spent for a visit, including the travel time to and from the clinic.

The restricted approval granted by the MCC limited participation to a research-experienced cohort, some of whom expected reimbursement levels similar to that of the efficacy trial from which they were drawn. Furthermore, participants had become accustomed to the rands 150 flat rate, and were less knowledgeable that reimbursement should cover direct costs, time, travel and inconvenience. Some participants felt that the reimbursement amount was reflective of the researchers appreciation of their participation, hence, the demoralisation when the reimbursement rate was reduced. The restricted approval made the study findings less generalisable, but also made an assessment of interest in the gel, outside of a trial with reimbursement, more challenging. Unlicensed tenofovir gel can only be distributed in South Africa within the confines of a clinical trial, the logistical and budgetary restrictions of which made implementation at local clinics less likely. Most participants had to travel to reach the designated public sector and research clinics, which increased costs and limited the approximation of real-world settings.

Limited empirical work has been conducted on participant reimbursements in general in South Africa, with no work on reimbursement specific to combined postaccess and implementation science trials. This results in the lack of systematic data collection using standardised validated tools. Instead, study decisions on reimbursement are informed by a collection of experiences of site staff, subjective interpretation of existing guidelines, reports from various meetings and community and participant input as the issue unfolded, which could be subject to bias. The swift reaction by CAPRISA staff on every level was a definite strength in strategically addressing participant concerns. A review of the wider literature examining reimbursement regulations and guidelines in the USA, Japan, Europe and Australia reveals that these documents advise the ethics committees to assess whether payment is an undue inducement or not, but have very little detailed guidance on how much or when payment should be made.13–15 Furthermore, in an analysis of current US policies, only 37.5% of organisations reported having written policies or guidelines on reimbursement, which was mostly done based on time (87%), inconvenience (84%) and less so on travel (68%).16

Combining a postaccess trial with an implementation trial was informed by the obligation that researchers have to provide post-trial access to proven effective products and the dire need to inform efficient programmatic roll out of a proven HIV prevention technology in a high-risk endemic setting, where options for HIV prevention that are women initiated and controlled are limited. The protracted regulatory review, punctuated by requests for face-to-face meetings with investigators and a regulator-hosted scientific review of the technology, is indicative of the novelty of this approach even for the regulator, especially against the background of recent unsuccessful microbicide trials.17 ,18 The researchers in an effort to ensure timely post-trial access did not factor in the change in transport costs during this delay.

A positive finding emanating from the reimbursement issue within CAPRISA 008 was the quality and timeliness of the engagement between study staff and the participants after participant complaints and the impact on retention, which demonstrates the importance CAPRISA places on the continued collaboration between research staff and participants in the conduct of study protocols. While this swift reaction by staff on every level was a definite strength in strategically addressing participant concerns, it remains clear that many of these concerns could have been pre-empted if the rise in the inflation rate and cost of living had been factored into the reimbursement prior to study initiation, given the delays in regulatory approval.